Evaluating the Safety, Tolerability, and Disposition of Trazpiroben, a D2 /D3 Receptor Antagonist: Phase I Single- and Multiple-Ascending Dose Studies in Healthy Japanese Participants

Abstract

Trazpiroben (TAK-906) is a peripherally selective dopamine D2 /D3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, parallel-group study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy Japanese men. Findings were compared with those from a prior US trial in healthy individuals. Overall, 24 participants were enrolled into 3 cohorts (each n = 8). Per cohort, 6 participants received trazpiroben (cohort 1, 50 mg; 2, 100 mg; 3, 10 mg) once on day 1 and twice daily on days 3 through 7, and two received placebo. Trazpiroben was well tolerated, with no clinically meaningful adverse events observed. Following single- and multiple-dose administration, trazpiroben was rapidly absorbed and eliminated (mean elimination half-life, 1.89-6.45 hours; median time to maximum serum concentration [steady state], 1.00-1.25 hours). Serum prolactin increased with trazpiroben treatment (mean maximum serum concentration 93.32 ng/mL [10 mg] vs. 10.83 ng/mL [placebo]), illustrating receptor target engagement. Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile. Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations, with further evaluation ongoing in a phase IIb study (NCT03544229).

Keywords: gastroparesis; pharmacodynamics; pharmacokinetics; safety; trazpiroben.

Conflict of interest statement

Y.T. and K.K. are employees of Takeda Pharmaceutical Company Ltd. and receive stock or stock options. O.H. was an employee of PRA Development Center KK at the time of the study. He is currently an employee of Alexion Pharma GK. C.C. was an employee of Takeda Development Center Americas, Inc., and received stock or stock options at the time of the study. He is currently an employee of Bayer Pharmaceuticals. R.W., a former shareholder of Altos Therapeutics LLC, will benefit from any future payments by Takeda with respect to certain clinical development and commercial milestones for trazpiroben. R.W. has received consulting fees from Takeda. S.H. is an employee of Houeikai Medical Corporation. Y.T., K.K., O.H., C.C., R.W., and S.H. have agreements with Takeda not to publish any Takeda‐sponsored research without prior authorization.

© 2021 Takeda Pharmaceutical Company Limited. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean (SD) plasma concentration–time curves of trazpiroben following single and multiple doses in Japanese participants. Plasma concentrations below the lower limit of quantification (0.05 ng/mL) were assigned a value of 0 ng/mL. SD, standard deviation.

Figure 2

Mean plasma concentration–time curves of trazpiroben following single and multiple doses in Japanese and US participants. Predose samples were assigned a sampling time of 0 hours. Plasma concentrations below the lower limit of quantification (0.05 ng/mL) were assigned a value of 0 ng/mL.

Figure 3

Mean serum concentration of prolactin following administration of single and multiple doses of trazpiroben in Japanese and US participants. Predose samples were assigned a sampling time of 0 hours.